Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
  • C07D471/14—Ortho-condensed systems
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
  • A61P35/02—Antineoplastic agents specific for leukemia

Definitions

• HHSN27200700038C AI077644, AI079436, and AI094348, awarded by the National Institutes of Health.
• the U.S. government has certain rights in the invention.
• TRAIL is an immunosurveillence cytokine critically involved in this process due to its ability to selectively induce apoptosis in cancer cells over normal cells
• the TRAIL gene is expressed in a variety of tissues and cells (S. R. Wiley, K. Schooley, P. J. Smolak, W. S. Din, C. P. Huang, J. K. Nicholl, G. R. Sutherland, T.
• the invention is directed, in various embodiments, to a compound and pharmaceutical composition comprising an effective amount of a compound capable of inducing expression of TRAIL gene in cells capable of expressing the TRAIL gene to produce the cytokine TRAIL.
• TRAIL a cytokine
• TRAIL can selectively induce apoptosis in cancer cells over normal cells. Therefore, the present disclosure provides a compound and pharmaceutical that is effective for treating various cancers. Without being bound by theory, the disclosed compound and pharmaceutical composition induces expression of TRAIL.
• the invention is directed to a compound of formula (I)
• Cyc is a single 5- to 8-membered heterocyclyl ring comprising at least one nitrogen atom, with a group of formula Ar 1 -CR 2 -being bonded to the nitrogen atom;
• Ar 1 and Ar 2 are each independently selected aryl groups which are independently substituted with 0, 1, or 2 J groups;
• each independently selected R is H or is (Cl-C6)alkyl
• J is (Cl-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(Cl-C6)alkyl, or halo; or a pharmaceutically acceptable salt thereof.
• the present disclosure provides a pharmaceutical composition comprising a
• the IUPAC name for compound 2 is 7- benzyl-4-(2-methylbenzyl)-l , 2,6,7,8 ,9-hexahydro imidazo[l,2-a]pyrido[3,4-e]pyrimidin- 5(4H)-one.
• the present disclosure provides a method for treating various cancers, comprising administering to a patient an effective amount of a compound of formula (I), such as compound 2.
• a broad spectrum of mammalian cancers wherein the broad spectrum of mammalian cancers to be treated is selected from the group consisting of ovarian, colon, breast, liver, pancreas, gastro-intestinal, head-and neck, cervix, prostate, lung cancers, melanomas, glioblastomas, myelomas, neuroblastic- derived CNS tumors, monocytic leukemias, B-cell derived leukemias, T-cell derived leukemias, B-cell derived lymphomas, T-cell derived lymphomas, and mast cell derived tumors, and combinations thereof.
• Figure 1 shows a) Induction of TRAIL mRNA in RAW cells treated for 48 h with indicated dose of linear isomer (1) or angular isomer 2; b) Induction of TRAIL mRNA induction to 5 ⁇ compound 1 and compound 2 for indicated times, c) Dose- dependent response to angular (2) and (9).
• Compound 2a is a sample obtained from the NCI repository, compound 2b is a compound synthesized herein; both were shown to be a compound of structure 2.
• Figure 2 shows a comparison of the imidazolinopyrimidanone structures of inactive compound 1 and active compound 2 with respect to TRAIL expression. The structures of each were confirmed by X-ray crystallographic analysis.
• Figure 3 shows the structure of constitutional isomer, compound 9.
• Figure 4 shows comparative structures of compound 1 and compound 2.
• Figure 5 shows the X-ray crystal structure obtained for compound 2.
• Figure 6 shows the X-ray crystal structure obtained for compound 9.
• Figure 7 shows a cell viability assay comparing the activity of a 20 mM concentration of various compounds including Compound 2 (HIPPO) and compounds A through R herein.
• HIPPO Compound 2
• Cyc is a 5- to 8-membered monocyclic heterocyclyl ring comprising one nitrogen atom, with a group of formula Ar 1 -CR 2 -being bonded to the ring nitrogen atom;
• Ar 1 and Ar 2 are each independently aryl groups which are substituted with 0, 1 , or 2 J groups;
• R is independently H or (Cl-C6)alkyl
• J is independently (Cl-C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(Cl- C6)alkyl, halo, or (Cl-C6)haloalkyl;
• the compound of formula (I) is a compound within the subgenus formula (IA)
• the compound of formula (IA) is a compound wherein Ar 1 and Ar are each a phenyl group substituted with 0, 1 , or 2 J groups; and,
• R at each occurrence is independently H or (Cl -C6)alkyl
• the compound of formula (I) is compound 2
• the invention provides a compound of formula (I) that is not compound 2.
• the present disclosure further provides a method for treating various cancers, comprising administering an effective amount of a compound of formula (I)
• Cyc is a 5- to 8-membered monocyclic heterocyclyl ring comprising one nitrogen atom, with a group of formula Ar ⁇ CR ⁇ -being bonded to the nitrogen atom;
• Ar 1 and Ar 2 are aryl groups which are substituted with 0, 1 , or 2 J groups;
• R is independently H or (Cl -C6)alkyl
• J is independently (Cl -C6)alkyl, (C3-C9)cycloalkyl, (C3-C9)cycloalkyl(Cl - C6)alkyl, halo, or (Cl-C6)haloalkyl; or a pharmaceutically acceptable salt thereof.
• the compound is a compound selected from the subgenus of formula
• Ar 1 and Ar 2 is a phenyl group substituted with 0, 1, or 2 J groups.
• the invention provides a method for treating various cancers with a compound of formula (I) wherein the compound of formula (I) is not compound 2.
• the method can be used for treating a broad spectrum of mammalian cancers, wherein the broad spectrum of mammalian cancers to be treated is selected from the group consisting of ovarian, colon, breast, liver, pancreas, gastro-intestinal, head-and neck, cervix, prostate, lung cancers, melanomas, glioblastomas, myelomas, neuroblasts - derived CNS tumors, monocytic leukemias, B-cell derived leukemias, T-cell derived leukemias, B-cell derived lymphomas, T-cell derived lymphomas, and mast cell derived tumors, and combinations thereof.
• the broad spectrum of mammalian cancers to be treated is selected from the group consisting of ovarian, colon, breast, liver, pancreas, gastro-intestinal, head-and neck, cervix, prostate, lung cancers, melanomas, glioblastomas, myelomas, neuroblasts - derived CNS tumor
• angular compound 2 (shown by the inventors herein to be the active TRAIL induction factor) has the structure
• Compound 1 (does not seem to be active) has the structure
• TRAIL disease or disorder or disorder
• malcondition are used interchangeably, and are used to refer to diseases or conditions wherein TRAIL, such as inducing expression of the TRAIL gene in a cell, plays a role in the biochemical mechanisms involved in the disease or malcondition or symptom(s) thereof such that a therapeutically beneficial effect can be achieved with an effective amount or concentration of a synthetic ligand of the invention adequate to induce expression of TRAIL and induce apoptosis, e.g., selectively in cancer cells.
• the cancers to be treated by the compounds of the present disclosure include a broad spectrum of mammalian cancers, wherein the broad spectrum of mammalian cancers to be treated is selected from the group consisting of ovarian, colon, breast, lung cancers, myelomas, neuroblastic-derived CNS
• tumors monocytic leukemias, B-cell derivedleukemias, T-cell derived leukemias, B-cell derived lymphomas, T-cell derived lymphomas, and mast cell derived tumors, and combinations thereof.
• the expression "effective amount”, when used to describe therapy to an individual suffering from a disorder, refers to the quantity or concentration of a compound of the invention that is effective to induce expression of TRAIL in the individual's tissues.
• a “salt” as is well known in the art includes an organic compound such as a carboxylic acid, a sulfonic acid, or an amine, in ionic form, in combination with a counterion.
• acids in their anionic form can form salts with cations such as metal cations, for example sodium, potassium, and the like; with ammonium salts such as NH 4 + or the cations of various amines, including tetraalkyl ammonium salts such as tetramethylammonium, or other cations such as trimethylsulfonium, and the like.
• a “pharmaceutically acceptable” or “pharmacologically acceptable” salt is a salt formed from an ion that has been approved for human consumption and is generally non-toxic, such as a chloride salt or a sodium salt.
• a “zwitterion” is an internal salt such as can be formed in a molecule that has at least two ionizable groups, one forming an anion and the other a cation, which serve to balance each other. For example, amino acids such as glycine can exist in a zwitterionic form.
• a “zwitterion” is a salt within the meaning herein.
• the compounds of the present invention may take the form of salts.
• the term “salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be “pharmaceutically-acceptable salts. " The term “salts" embraces addition salts of free acids or free bases which are compounds of the invention. Salts can be “pharmaceutically-acceptable salts. " The
• “pharmaceutically-acceptable salt” refers to salts which possess toxicity profiles within a range that affords utility in pharmaceutical applications. Pharmaceutically unacceptable salts may nonetheless possess properties such as high crystallinity, which have utility in the practice of the present invention, such as for example utility in process of synthesis, purification or formulation of compounds of the invention.
• “Pharmaceutically or pharmacologically acceptable” include molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or a human, as appropriate.
• preparations should meet sterility, pyrogenicity, and general safety and purity standards as required by FDA Office of Biologies standards.
• High-resolution mass spectra were recorded on Agilent LC/MSD TOF mass spectrometer by electrospray ionization time-of-flight reflectron experiments.
• IR spectra were recorded on either a PerkinElmer Spectrum 100 FTIR spectrometer with ATR accessory or a Jasco 480 Plus FTIR spectrometer. Melting points were recorded on a Fisher-Johns 12-144 melting point apparatus and are uncorrected.
• SHELXT Solution by direct methods
• a colorless crystal of compound 9 was mounted on a Cryoloop with Paratone oil and data was collected at 100 K on a Bruker APEX II CCD with Mo K a radiation (generated from a Mo rotating anode). Data was corrected for absorption with SADABS and structure was solved by direct methods.
• RAW 264.7 cells (ATCC TIB-71) were maintained in growth medium of Dulbecco's Modified Eagle's Medium (DMEM with 4.5 g/L glucose and pyruvate, Gibco BRL, Invitrogen Corp., USA) supplemented with L-glutamine,
• DMEM Dulbecco's Modified Eagle's Medium
• RNA concentration determined using a Hitachi U- 2000 UV-Vis Spectrophotometer and samples diluted to 12 ⁇ g / 5 ⁇ in H20. This solution was diluted 1 :5 in H 2 0 and 1 ⁇ of this solution was mixed with 50 ⁇ of RT- PCR reaction mixture (Qiagen Onestep RT-PCR kit) and TRAIL primers
• mTRAIL-F 5 ' -GACACCATTTCTACAGTTCCAG-3 ' (SEQ ID NO. 1)
• mTRAIL-R 5 ' -CGGATAGCTGGTGTACTTGTAG-3 ' 3' (SEQ ID NO. 2).
• hTrail-F2 5 ' - ACAGACCTGCGTGCTGATCGTG-3 ' 3' (SEQ ID NO. 3) (exon 1)
• hTrail-R2 5 ' - ACGAGCTGACGGAGTTGCCAC-3 ' 3' (SEQ ID NO. 4) (exon 2).
• RT-PCR was run on an Applied Biosystems Gene Amp 9700 PCR system.
• PCR products were analyzed on 5.5% acrylamide gel in TAE buffer (T. Maniatis, E. F. Fritsch, J. Sambrook, Molecular Cloning: a Laboratory Manual, Cold Spring Harbor Laboratory, Cold Spring Harbor, 1989).
• RAW 264.7 cells were plated at -500 cell/well in Costar 96-well plates (Corning Inc, NY) in phenol-free Dulbecco's Modified Eagle's Medium (DMEM with 4.5 g/L glucose, Gibco BRL, Invitrogen Corporation, USA) supplemented with 10% fetal bovine serum (Gibco BRL, Invitrogen Corp., USA), L-gluatamine, pyruvate,

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